Nonpeptide Renin Inhibitors Employing a Novel 3-aza(or oxa)-2,4-dialkyl Glutaric Acid Moiety as a P2/P3 Amide Bond Replacement

J Med Chem. 1992 May 15;35(10):1722-34. doi: 10.1021/jm00088a006.

Abstract

A new series of renin inhibitors has been developed. The inhibitors feature a novel replacement for the P2/P3 dipeptide moiety normally associated with renin inhibitors. The dipeptide replacement was a (2S,4S)-3-aza(or oxa)-2,4-dialkylglutaric acid amide. Extensive structure-activity relationship studies determined that optimum potency was achieved when inhibitors employed a benzyl and butyl group at the C(4) and C(2) carbon position, respectively. In addition, maximum in vitro potency was obtained when the N-terminus was functionalized by incorporating a 4-(1,3-dioxabutyl)piperidine amide. SAR data suggested that the 1,3-dioxabutyl group (methoxymethyl ether) interacted by hydrogen bonding to groups in the S4 domain of renin. This hypothesis was strengthened when a 4-butylpiperidine amide was substituted and inhibitor potency decreased dramatically. Inhibitors employing this novel dipeptide mimic were prepared by coupling the glutaric acid amides with either the transition-state mimic (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6- methylheptane (18) or the hydroxyethylene dipeptide isostere. The glutaric acid amides were prepared by two general procedures. The first procedure involved the reductive amination of alpha-amino acid esters with alpha-keto esters. The second procedure involved the displacement reaction of alpha-bromo esters or acids with alpha-amino acid amides.

MeSH terms

  • Amides / chemistry*
  • Amino Acid Sequence
  • Animals
  • Biological Availability
  • Blood Pressure / drug effects
  • Dipeptides / pharmacology
  • Enalapril / pharmacology
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Glutarates / chemistry*
  • Glutarates / pharmacology
  • Macaca fascicularis
  • Male
  • Molecular Sequence Data
  • Renin / antagonists & inhibitors*
  • Renin / metabolism
  • Renin-Angiotensin System
  • Structure-Activity Relationship

Substances

  • Amides
  • Dipeptides
  • Enzyme Inhibitors
  • Glutarates
  • enalkiren
  • Enalapril
  • Renin